Impact of haemoglobin variants on the diagnostic sensitivity of glycated haemoglobin (HbA1c) assay methodologies in sub-Saharan Africa: a laboratory-based method validation study.

Introduction: the utility of glycated haemoglobin (HbA1c) for the diagnosis and monitoring of diabetes in sub-Saharan Africa is uncertain due to limited data on the performance of the available HbA1c assay methods in this population, which has a high prevalence of haemoglobin variants. We aimed to compare the diagnostic accuracy of the major HbA1c methodologies (Boronate Affinity, Capillary Electrophoresis, High Performance Liquid Chromatography, Immunoassay) in an African population, and assess the impact of the common haemoglobin variant HbAS (sickle cell trait). Methods: whole blood samples were obtained from 182 individuals living with type 2 diabetes in Uganda. HbA1c values for each method were compared to average glucose measured over 14 days by continuous glucose monitoring (CGM). To determine concordance, the three HbA1c assay methods were compared to the capillary electrophoresis method. Results: there was a strong correlation between CGM average glucose levels and all four HbA1c methodologies (r=0.81-0.89) which did not differ in those with and without HbAS (present in 37/182 participants). The presence of HbAS did not alter the relationship between HbA1c and CGM glucose for any assay (p for interaction >0.2 for all methods). Diagnostic accuracy for CGM average glucose thresholds of 7 and 10mmol/L was similar across methods (area under the receiver operating characteristic curve 0.80-0.84 and 0.76-0.84 respectively). The maximum bias between the HbA1c assay methodologies was 2 mmol/mol (2.07%). Conclusion: all major HbA1c technologies offer accurate and comparable HbA1c measurement even in this population with high prevalence of haemoglobin variants.

Waist circumference and glycaemia are strong predictors of progression to diabetes in individuals with prediabetes in sub-Saharan Africa: 4-year prospective cohort study in Malawi.

Sub-Saharan Africa is projected to have the highest increase in the number of people with diabetes worldwide. However, the drivers of diabetes in this region have not been clearly elucidated. The aim of this study was to evaluate the incidence of diabetes and the predictors of progression in a population-based cohort with impaired fasting glucose (IFG) in Malawi. We used data from an extensive rural and urban non-communicable disease survey. One hundred seventy-five, of 389 individuals with impaired fasting glucose (IFG) at baseline, age 48 ±15 years and body mass index 27.5 ±5.9 kg/m2 were followed up for a median of 4.2 years (714 person-years). Incidence rates were calculated, and predictors of progression to diabetes were analysed using multivariable logistic regression models, with overall performance determined using receiver operator characteristics (ROC) curves. The median follow-up was 4.2 (IQR 3.4-4.7) years. Forty-five out of 175 (26%) progressed to diabetes. Incidence rates of diabetes were 62.9 per 1000 person-years 95% CI, 47.0-84.3. The predictors of progression were higher; age (odds ratio [OR] 1.48, P = 0.046), BMI (OR 1.98, P = 0.001), waist circumference (OR 2.50,P<0.001), waist-hip ratio (OR 1.40, P = 0.03), systolic blood pressure (OR 1.56, P = 0.01), fasting plasma glucose (OR 1.53, P = 0.01), cholesterol (OR 1.44, P = 0.05) and low-density lipoprotein cholesterol (OR 1.80, P = 0.002). A simple model combining fasting plasma glucose and waist circumference was predictive of progression to diabetes (ROC area under the curve = 0.79). The incidence of diabetes in people with IFG is high in Malawi and predictors of progression are like those seen in other populations. Our data also suggests that a simple chart with probabilities of progression to diabetes based on waist circumference and fasting plasma glucose could be used to identify those at risk of progression in clinical settings in sub-Saharan Africa.

Real-world effectiveness of pneumococcal vaccination in older adults: Cohort study using the UK Clinical Practice Research Datalink.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for UK older adults, but how age moderates effectiveness is unclear. METHODS: Three annual cohorts of primary-care patients aged≥65y from the Clinical Practice Research Datalink selected from 2003-5 created a natural experiment (n = 324,804), reflecting the staged introduction of the vaccine. The outcome was symptoms consistent with community-acquired pneumococcal pneumonia (CAP) requiring antibiotics or hospitalisation. We used the prior event rate ratio (PERR) approach to address bias from unmeasured confounders. RESULTS: Vaccinated patients had higher rates of CAP in the year before vaccination than their controls, indicating the potential for confounding bias. After adjustment for confounding using the prior event rate ratio (PERR) method, PPV23 was estimated to be effective against CAP for two years after vaccination in all age sub-groups with hazard ratios (95% confidence intervals) of 0.86 (0.80 to 0.93), 0.74 (0.65 to 0.85) and 0.65 (0.57 to 0.74) in patients aged 65-74, 75-79 and 80+ respectively in the 2005 cohort. Age moderated the effect of vaccination with predicted risk reductions of 8% at 65y and 29% at 80y. CONCLUSIONS: PPV23 is moderately effective at reducing CAP among UK patients aged≥65y, in the two years after vaccination. Vaccine effectiveness is maintained, and may increase, in the oldest age groups in step with increasing susceptibility to CAP.

Influenza vaccination reduced myocardial infarctions in United Kingdom older adults: a prior event rate ratio study.

OBJECTIVES: We aimed to estimate the real-world effectiveness of the influenza vaccine against myocardial infarction (MI) and influenza in the decade since adults aged ≥ 65 years were first recommended the vaccine. STUDY DESIGN AND SETTING: We identified annual cohorts, 1997 to 2011, of adults aged ≥ 65 years, without previous influenza vaccination, from UK general practices, registered with the Clinical Practice Research Datalink. Using a quasi-experimental study design to control for confounding bias, we estimated influenza vaccine effectiveness on hospitalization for MI, influenza, and antibiotic prescriptions for lower respiratory tract infections. RESULTS: Vaccination was moderately effective against influenza, the prior event rate ratio-adjusted hazard ratios ranging from 0.70 in 1999 to 0.99 in 2001. Prior event rate ratio-adjusted hazard ratios demonstrated a protective effect against MIs, varying between 0.40 in 2010 and 0.89 in 2001. Aggregated across the cohorts, influenza vaccination reduced the risk of MIs by 39% (95% confidence interval: 34%, 44%). CONCLUSION: Effectiveness of the flu vaccine in preventing MIs in older UK adults is consistent with the limited evidence from clinical trials. Similar trends in effectiveness against influenza and against MIs suggest the risk of influenza mediates the effectiveness against MIs, although divergence in some years implies the mechanism may be complex.

Continuous glucose monitoring demonstrates low risk of clinically significant hypoglycemia associated with sulphonylurea treatment in an African type 2 diabetes population: results from the OPTIMAL observational multicenter study.

INTRODUCTION: People living with diabetes in low-resource settings may be at increased hypoglycemia risk due to food insecurity and limited access to glucose monitoring. We aimed to assess hypoglycemia risk associated with sulphonylurea (SU) and insulin therapy in people living with type 2 diabetes in a low-resource sub-Saharan African setting. RESEARCH DESIGN AND METHODS: This study was conducted in the outpatients' diabetes clinics of two hospitals (one rural and one urban) in Uganda. We used blinded continuous glucose monitoring (CGM) and self-report to compare hypoglycemia rates and duration in 179 type 2 diabetes patients treated with sulphonylureas (n=100) and insulin (n=51) in comparison with those treated with metformin only (n=28). CGM-assessed hypoglycemia was defined as minutes per week below 3mmol/L (54mg/dL) and number of hypoglycemic events below 3.0 mmol/L (54 mg/dL) for at least 15 minutes. RESULTS: CGM recorded hypoglycemia was infrequent in SU-treated participants and did not differ from metformin: median minutes/week of glucose <3 mmol/L were 39.2, 17.0 and 127.5 for metformin, sulphonylurea and insulin, respectively (metformin vs sulphonylurea, p=0.6). Hypoglycemia risk was strongly related to glycated haemoglobin (HbA1c) and fasting glucose, with most episodes occurring in those with tight glycemic control. After adjusting for HbA1c, time <3 mmol/L was 2.1 (95% CI 0.9 to 4.7) and 5.5 (95% CI 2.4 to 12.6) times greater with sulphonylurea and insulin, respectively, than metformin alone. CONCLUSIONS: In a low-resource sub-Saharan African setting, hypoglycemia is infrequent among people with type 2 diabetes receiving sulphonylurea treatment, and the modest excess occurs predominantly in those with tight glycemic control.

Short-term exposure to soils and sludge induce changes to plastic morphology and 13C stable isotopic composition.

There is concern about the buildup of plastic waste in soil, their degradation into microplastics, and their potential to interfere with the natural processing of soil organic carbon and other nutrient cycling processes. Here we used scanning electron microscopy (SEM) and 13C isotope ratio mass spectrometry to determine if precut consumer plastics comprised of either high density polyethylene (HDPE), a blend of linear low density polyethylene and low density polyethylene (L/LDPE), or polyethylene terephthalate (PETE) would degrade or transform during a short-term, 32 day, exposure to soil or sludge in laboratory microcosms. SEM confirmed morphological changes occurred to all plastics, but the attachment of biofilm and presence of microorganisms mostly favored PETE and HDPE surfaces. These observations support the idea that abiotic and/or biotic processes may degrade plastics in soil; however distinguishable and significant changes in mean stable isotopic values (Δδ13C) of ~0.2-0.7‰ were only observed for exposed PETE and HDPE. This indicates that each plastic's degradation in soil may be dependent on their physical and chemical properties, with L/LDPE being more resistant and less prone to degradation compared to the others, and less dependent on the environmental conditions or properties of the soil or sludge. Our experiments were short-term and while the mechanisms of degradation are not clear, the results provide strong motivation for further studies of plastic fate and processing in soil systems. Direct mechanistic studies using stable isotopic approaches in combination with other characterizations and techniques are clearly warranted and may lead to a significant enhancement in our present understanding of the interactions and dynamics of plastics in the soil environment.

HbA1c performs well in monitoring glucose control even in populations with high prevalence of medical conditions that may alter its reliability: the OPTIMAL observational multicenter study.

INTRODUCTION: The utility of HbA1c (glycosylated hemoglobin) to estimate glycemic control in populations of African and other low-resource countries has been questioned because of high prevalence of other medical conditions that may affect its reliability. Using continuous glucose monitoring (CGM), we aimed to determine the comparative performance of HbA1c, fasting plasma glucose (FPG) (within 5 hours of a meal) and random non-fasting glucose (RPG) in assessing glycemic burden. RESEARCH DESIGN AND METHODS: We assessed the performance of HbA1c, FPG and RPG in comparison to CGM mean glucose in 192 Ugandan participants with type 2 diabetes. Analysis was undertaken in all participants, and in subgroups with and without medical conditions reported to affect HbA1c reliability. We then assessed the performance of FPG and RPG, and optimal thresholds, in comparison to HbA1c in participants without medical conditions thought to alter HbA1c reliability. RESULTS: 32.8% (63/192) of participants had medical conditions that may affect HbA1c reliability: anemia 9.4% (18/192), sickle cell trait and/or hemoglobin C (HbC) 22.4% (43/192), or renal impairment 6.3% (12/192). Despite high prevalence of medical conditions thought to affect HbA1c reliability, HbA1c had the strongest correlation with CGM measured glucose in day-to-day living (0.88, 95% CI 0.84 to 0.91), followed by FPG (0.82, 95% CI 0.76 to 0.86) and RPG (0.76, 95% CI 0.69 to 0.81). Among participants without conditions thought to affect HbA1c reliability, FPG and RPG had a similar diagnostic performance in identifying poor glycemic control defined by a range of HbA1c thresholds. FPG of ≥7.1 mmol/L and RPG of ≥10.5 mmol/L correctly identified 78.2% and 78.8%, respectively, of patients with an HbA1c of ≥7.0%. CONCLUSIONS: HbA1c is the optimal test for monitoring glucose control even in low-income and middle-income countries where medical conditions that may alter its reliability are prevalent; FPG and RPG are valuable alternatives where HbA1c is not available.

Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study.

BACKGROUND: Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the 'intermediate' range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D. METHODS: We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model. RESULTS: The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified 'high-risk' with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44-47 mmol/mol [6.2-6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39-41 mmol/mol (5.7-5.9%) and 7.0% (5.4, 8.6%) for 42-43 mmol/mol (6.0-6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7-6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%). CONCLUSIONS: A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.

Associations between low HDL, sex and cardiovascular risk markers are substantially different in sub-Saharan Africa and the UK: analysis of four population studies.

INTRODUCTION: Low high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, although this relationship is not causal and is likely mediated through associations with other risk factors. Low HDL is extremely common in sub-Saharan African populations, and this has often been interpreted to indicate that these populations will have increased cardiovascular risk. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK. METHODS: We compared data from adults living in Uganda and Malawi (n=26 216) and in the UK (n=8747). We examined unadjusted and adjusted levels of HDL and applied the WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors. RESULTS: HDL was substantially lower in the African than in the European studies (geometric mean 0.9-1.2 mmol/L vs 1.3-1.8 mmol/L), with African prevalence of low HDL as high as 77%. Total cholesterol was also substantially lower (geometric mean 3.3-3.9 mmol/L vs 4.6-5.4 mmol/L). In comparison with European studies the relationship between HDL and adiposity (body mass index, waist to hip ratio) was greatly attenuated in African studies and the relationship with non-HDL cholesterol reversed: in African studies low HDL was associated with lower non-HDL cholesterol. The association between sex and HDL was also different; using the WHO sex-specific definitions, low HDL was substantially more common among women (69%-77%) than men (41%-59%) in Uganda/Malawi. CONCLUSION: The relationship between HDL and sex, adiposity and non-HDL cholesterol in sub-Saharan Africa is different from European populations. In sub-Saharan Africans low HDL is a marker of low overall cholesterol and sex differences are markedly attenuated. Therefore low HDL in isolation is unlikely to indicate raised cardiovascular risk and the WHO sex-based cut-offs are inappropriate.

Moving through Motherhood: Involving the Public in Research to Inform Physical Activity Promotion throughout Pregnancy and Beyond.

Information received by women regarding physical activity during and after pregnancy often lacks clarity and may be conflicting and confusing. Without clear, engaging, accessible guidance centred on the experiences of pregnancy and parenting, the benefits of physical activity can be lost. We describe a collaborative process to inform the design of evidence-based, user-centred physical activity resources which reflect diverse experiences of pregnancy and early parenthood. Two iterative, collaborative phases involving patient and public involvement (PPI) workshops, a scoping survey (n = 553) and stakeholder events engaged women and maternity, policy and physical activity stakeholders to inform pilot resource development. These activities shaped understanding of challenges experienced by maternity and physical activity service providers, pregnant women and new mothers in relation to supporting physical activity. Working collaboratively with women and stakeholders, we co-designed pilot resources and identified important considerations for future resource development. Outcomes and lessons learned from this process will inform further work to support physical activity during pregnancy and beyond, but also wider health research where such collaborative approaches are important. We hope that drawing on our experiences and sharing outcomes from this work provide useful information for researchers, healthcare professionals, policy makers and those involved in supporting physical activity behaviour.